Mast cells play a critical role in asthma and allergic disorders by releasing pro-inflammatory mediators and cytokines. Antigen-mediated aggregation of FcεRI, the high-affinity receptor for IgE results in activation of mast cells. This triggers a series of signaling events resulting in the release of mediators, including histamine, proteases, leukotrienes and cytokines. These mediators cause increased vascular permeability, mucus production, bronchoconstriction, tissue degradation and inflammation, thus playing key roles in the etiology and symptoms of asthma and allergic disorders.
One of the key events in the signaling pathway following the activation of mast cells is activation of the tyrosine kinase SYK. SYK kinase acts as a central initiator of all subsequent signaling leading to mediator release. The critical role of SYK kinase in the signaling path was demonstrated by the complete inhibition of mediator release by a protein containing the SH2 domains of SYK kinase that functioned as an inhibitor of SYK kinase (J. A. Taylor et al., Molec. and Cell Biol., 1995, 15, 4149). Furthermore, direct clustering of SYK, introduced into a mast cell line as part of a chimeric transmembrane protein, was found to be sufficient to stimulate the events leading to mediator release normally induced by clustering of FcεRI (V. M. Rivera and J. S. Brugge, Molec. and Cell. Biol., 1995, 15, 1582).
ER-27319 (3,4-dimethyl-10-(3-aminopropyl)-9-acridone oxalate), a compound reported to interfere with the activation of SYK, has been shown to inhibit anti-IgE mediated degranulation in rodent and human mast cells (K. Moriya et al., Proc. Nat. Acad. Sci. USA, 1997, 94, 12539). Concentrations of piceatannol (3,4,3′5′-tetrahydroxy-trans-stilbene), a non-selective SYK kinase inhibitor, that inhibited the antigen-stimulated phosphorlation of SYK also inhibited functional responses in mast cells, including mediator release (J. M. Oliver et. al., J. Biol. Chem., 1994, 269, 29697).
The conclusion from the studies described above is that SYK kinase activation and activity is required for FcεRI-mediated release of mediators from mast cells. Therefore, agents that block the activity of SYK kinase act to block the release of allergic and pro-inflammatory mediators and cytokines. These agents have potential utility in treating inflammatory and allergic disorders including asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, conjunctivitis, psoriasis, scleroderma, urticaria, dermatitis and allergic rhinitis.
In addition to the inhibitors mentioned above, WO 0109134 discloses purine derivatives as inhibitors of SYK kinase. WO 9931073 describes pyrimidine-5-carboxamide derivatives as inhibitors of SYK kinase. WO 0147922 describes substituted azaindoles useful in the treatment of disease states capable of being modulated by the inhibition of protein kinases, in particular SYK kinase. WO 9818782 describes inhibitors of ZAP70 that are also reported to inhibit SYK.
In addition to mast cells, SYK is expressed in other hematopoietic cells including B cells, where it is thought to play an essential role in transducing signals required for the transition of immature B cells into mature recirculating B cells (M. Turner et al., Immunology Today, 2000, 21, 148). B cells are reported to play an important role in some inflammatory conditions such as lupus (O. T. Chan et al., Immunological Rev., 1999, 169, 107) and rheumatoid arthritis (A. Gause and C. Borek, Biodrugs, 2001, 15, 73).
SYK was also reported to be an element of the signaling cascade in beta-amyloid and prion fibrils leading to production of neurotoxic products (C. K. Combs et al., J. Neurosci., 1999, 19, 928). Furthermore, an inhibitor of SYK blocked the production of these neurotoxic products. Thus a SYK inhibitor would potentially be useful in the treatment of Alzheimer's disease and related neuroinflammatory diseases. Another report (Y. Kuno et al., Blood, 2001, 97, 1050) demonstrates that SYK plays an important role in malignant progression. A TEL-SYK fusion protein was found to transform hematopoietic cells suggesting a role in the pathogenesis of hematopoietic malignancies. Therefore a SYK inhibitor may be useful in the treatment of certain types of cancers.
A recent report suggests that SYK is a mediator of epithelial cell growth and suggests that it could be a potential tumor-suppressor in human breast carcinomas (P. J. P. Coopman et al., Nature, 2000, 406, 742). One could conclude from this report that while inhibition of SYK kinase activity could be desirable for treatment of inflammatory and allergic disease and asthma, a complete, irreversible blockade of SYK kinase activity may not be desirable.
BE 835,770 describes 5-amino-1,6-naphthyridines having antimicrobial activity. U.S. Pat. No. 3,928,367, U.S. Pat. No. 4,017,500, U.S. Pat. No. 4,115,395 and U.S. Pat. No. 4,260,759 describe 5-amino-1,6-naphthyridines having antifungal and antibacterial activity. WO 9918077 describes 5-piperazinyl-1,6-naphthyridines as serotonin antagonists.